21-diazo-compounds for synthesizing steroids



atent O 2,832,??2 Patented Apr. 29, N58

intermediates in proceeding from a l7-formyl-cyclopent- 2,332,772 I:e301; c119,13 dimetl11%l(- A 1 dodec'iigiiirolplenant renemm to a acyoXy'acety y roxy- ZI'DIAZGCOMPOUNDB SYNTHESIZING cyclopentano 10,13dimethyl A dodecahydrophe- STERGIDS 5 nanthrene-3,11-dione by a processhereinafter described. Martin W. Farrar, Webster Groves, HmoldRafielson, In particular this invention relates to methods and novel andWilliam K Kifkwofld, compounds useful in the preparation of acylderivatives ass'gnors M9358!!! Chemical Company Loms of3,11,20-triketo-17,2l-dihydroxy-A -pregnene from 3,11- a corpmafion ofDelaware diketo-l7-forrnyl A -androstadiene. No Drawing. Originalapplication June 15, 18353, Serial 10 This invention will bedescribedwith respect to its N 361,828, PP Patent f 3 dated August preferredembodiment but it is to be understood that such 21, 1956. Divided andthis application June 1%, H56, is not limitative of this inventionSerial No. 591,820 Th e sequence of steps or series or reactionsproceeding 1 Claim. (Cl. 260-23955) 15 to a17-(acyloxyacety1)-17-hydroxy-cyclopentano-10,13- dimethyl-Adodecahydrophenanthrene-3,1l-dione for pur- This invention relates tomethods and novel steroidal P0568 of this invention is Outlinedschematically in the compounds of thecyclopentanodirnethylpolyhydrophenanfollowing diagram Proceeding from ay y threne series having a 3-keto group, a ll-keto group and a pent 16 010,13 imethyl A odecahydrophedouble bond in the 4,5 position, whichcompounds are 2 nanthren-3,11-dione.

CH0 CH0 COOK cool ' onion Hal CHIOB VIII The first step in the processas afore schematically outlined is the oxidation of3,1l-diketo-l7-formyl-A androstadiene (Compound I) to the 16,17-oxidoderivative (Compound II) employing approximately o'" chem.- icalequivalent of an oxygen-furnishing age such as the organic peracids orhydrogen peroxide. The oxidation is ordinarily carried out by mixing theoxidant and 3,1l-diketo-l7-formyl-?S -androstadine together in anorganic medium which is non-reactive under the reaction conditions.Suitable media include chloroform, carbon tetrachloride, diethyl ether,glacial acetic acid, methanol, ethanol, isopropanol, and the like. Thetemperature of the reaction may vary from l C. to 50 C. A convenientreaction medium when the oxidant is hydrogen peroxide is a low molecularweight alcohol.

As illustrative of this step is the following:

Ewm I To a suitable reaction vessel containing 200 parts by weight(substantially 0.64 mol) of til-3,1l-diketo-l7-.v

formyl-d -androstadiene dissolved in 240-1 parts by weight of methanolmaintained at a temperature of about 5-10 C. is added approximately 50parts by weight of 2.65 N sodium hydroxide followed by approximately 580parts by weight of a methanol-hydrogen peroxide mix containingapproximately 22.85 parts by weight of hydrogen peroxide. The mix soobtained is agitated for about hours at 0-5 C. Thereupon substantiallyall of the methanol is removed by vacuum distillation and the residue istaken up with chloroform. The chloroform solution is washed with waterand then dried over anhydrous magnesium sulfate. Upon evaporation of thechloroform there is obtained approximately 212 parts by weight of awhite crystalline material, which upon triturating with diethyl ethercontaining a small amount of chloroform yields white crystallinezil3,ll-diketo-16,l7- oxido-17-formyl d -androstene (M. P. 243-245 0.).

Similarly the individual optically active isomers such as the naturalmodification of 3,11-diketo-l6,l7-oxido-17- formyl-Mandrostene areobtained beginning with the individual optically active isomers of3,ll-diketo-l7- formyl-Z -androstadiene.

The next step in the process as afore schematically outlined is theoxidation of the 17-formyl group of the 16,17-oxido compound (Compound11) to form 3,11- diketo-16,17-oxido-Z -etiocholenic acid (Compound Hi).This step is readily brought about employing a mild oxidizing agent suchas silver oxide, sodium dichromate in acetic acid, etc.

As illustrative of the preparation of 3,1l-diketo-16,17- oxido-ii-etiocholenic acid is the following:

Example .11

To an intimate mixture containing approximately 570 parts by weight ofdioxane, approximately 570 parts by weight of 10% sodium hydroxide andapproximately 63.9 parts by weight of silver nitrate is slowly addedapproximately 60 parts by weight of iii-3,11-diketo-16,l7-oxido-17-formy1-. S androstenei Upon completion. of the addition of the16,17-oxido compound approximately 500 parts by weight of water andapproximately 500 parts by weight of dioxane is added with constantagitation. Thereafter the mix is agitated for about 1 hour at roomtemperature. The mix is filtered. The collected residue is washed withwater and the washings combined with the original filtrate, whichcombination is then extracted with several portions of diethyl ether.The ether extracts are discarded. The aqueous layer is then acidifiedand then extracted with chloroform. The chloroform extracts arecombined, dried, and subjected to vacuum distillation. Approximately 57parts by weight of a yellow crystalline solid is obtained. from whichupon triturating with a mixture of diethyl ether and ethyl acetate thereis obtained crystalline til-3,11-diketo-l6,l7-oxido-A -etio- 4 cholenicacid (M. P. 217-220 C. with decomposition).

In a similar manner the individual optically active isomers such as thenatural modification of 3,1l-diketol6,17-oxdio-Z -etiocholenic acid areobtained beginning with the individual optically active isomers of3,1l-dilcetol6, i7-oxidol7-formyl-ZS -androstene.

In the next step of the process as afore schematically outlined the acidhalide (Compound lV) of 3,1l-diketol6,l7-oxido-Zi -etiocholenic acid isprepared employing an acyl halide forming agent such as oxalyl chlorideand the like.

As illustrative of this step is the following:

Example III To a solution containing approximately parts by weight of(ll-3,1l-diketo-l6,l7-oxido-ii =etiocholenic acid in approximately 8000parts by weight of anhydrous methanol is added suflicient sodiummethylate to neutralize the epoxy acid. The methanol is removed byvacuum distillation and to the residue is added and intimately mixedapproximately 900 parts by weight of benzene and approximately 5 partsby weight of pyridine followed by approximately 500 parts by weight ofoxalyl chloride while maintaining the temperature at about 10 C. The mixso obtained is allowed to stand for about 30 minutes, whereupon the mixis subjected to vacuum distillation while maintaining the temperature atabout 15 C. The residue is then taken up with approximately 1000 partsby weight of benzene and again subjected to vacuum distillation at about15 C. The residue is then taken up with approximately 500 parts byweight of benzene and filtered. The filtrate is then subjected to vacuumdistillation. A crystalline residue, approximately 87 parts by weight,identified as the acid chloride of 111 3,].l-diketo-16,17-oxido A-etiocholenic acid (M. P. 222-224" C.), is obtained.

Similarly the individual optically active isomers such as the acidchloride of the natural modification of 3,11- diketo-l6,17-oxido-K-etiocholenic acid is obtained beginning with the individual opticallyactive isomers of 3,11- diketo-l6,17-oxid0-K -etiocholenic acid.

The next step of the process as afore schematically outlined is thepreparation of the diazo-ketone (Cornpound V), namely3,11,20-triketo-16,l7 oxido-2l-dioazo- K -pregnene, from the acid halideof 3,11-diketo-16,17- oxido d -etiocholenic acid. This process employsan excess of two chemical equivalents of diazomethane in converting theacid halide (Compound IV) to the desired diazo-ketone (Compound V) andis ordinarily carried out in an inert organic solvent such as ether,benzene, dioxane, toluene, and the like, and at a temperature in therange of -20 to 40 C.

As illustrative of the preparation of the diazo-ketone is the following:

Example IV To a suitable reaction vessel containing an ether solutioncontaining approximately 100 parts by weight of diazomethane is addedapproximately 50 parts by weight of the acid chloride oftil-3,11-diketo-16,17-oxid0-Z etiocholenic acid dissolved in 500 partsby weight of benzene while maintaining the temperature at about 0 C. Themixture so obtained is then agitated for about one hour at about 0 C.The mix is then subjected to vacuum distillation whereby a light yellowcrystalline residue, melting with decomposition at about C., identifiedas til-3,11,20-triketo-16,17-oxido-2l-diazo-h' pregnene is obtained.

Similarly the optically active isomers such as the natural modificationof 3,1LZO-triketo-l6,17-oxido-21-diazo-E pregnene are obtained beginningwith the acid halide of the appropriate individual optically activeisomers of 3,1 l-diketo-16,17-oxido-K -etiocholenic acid.

In the next step of the process as afore schematically outlined thediazo-ketone (Compound V) is decomposed sesame by heating inthe-presence of a carboxylic acid, whereby there'is obtained3,1l,ZO-triketo-16,17-oxido-21-acyloxy- 'Alpregnene.

where .R is an acyl radical obtained from a carboxylic acid such asacetic acid, propionic acid, butyric acid, valeri'c acid, caproic acid,lauric acid, stear'ic acid, phenylacetlc acid, fi-phenylpropioni'c'acid, benzoic acid, toluic acid, etc., upon removal of the hydroxy groupof the carboxyl group. Where desirable an inert organic solvent may beemployed such as benzene, toluene, xylene, dioxane.

As illustrative of this step is the following:

Example V To a suitable reaction vessel containing approximately 500parts by weight of acetic acid is added approximately 5 parts by weightof dl -3-,11,20-triketo-l6,17-oxido-21- diazo 'A -pregnene and the mixso obtained heated at about 90-95" C. for about 30 minutes. The mix isthen subjected to vacuum distillation. The resultant resithen washedwith aqueous sodium bicarbonate, then with water and dried. Thechloroform solution so treated is then subjected to vacuum distillationto remove the solvent. The non-crystalline residue so obtained isidentified as dl-3,11,20-triketo-l6,l7-oxido-21-acetyloxy 5- pregnene.

Similarly the individual optically active isomers such as the naturalmodification of 3,11,20-triketo-16,17-oxido- 2l-acetyloxy 'a pregneneare obtained beginning with the individual isomers of3,11,20-triketo-l6,17-oxido 21- diazo-h -pregn-ene.

In the next step of the process as afore schematically outlined the21-acyloxy compound (Compound V1) is reacted with a hydrogen halide suchas HCl, HBr or HI, to remove the epoxide grouping and provide thehalohydrin (Compound VII), namely 3,11,20-triketo-16-halo-17-hydroxy-2l-acyloxyQV-pregnene. This reaction is carried out in aninert organic solvent containing dissolved therein a hydrogen halide andat a temperature in the range of 20 C. to 40 C.

As illustrative of this step employing hydrogen bromide is thefollowing:

Example VI Approximately 4 parts by weight of dl-3,11,20-triketo-16,17-oxid-o-2l-acetyloxy fi -pregnene is admixed with approximately 300parts by weight of acetic acid and approximately 100 parts by weight ofbenzene in a suitable reaction vessel. Thereto is added whilemaintaining the temperature at about 0 C. approximately 8 parts byweight of a 38% acetic acid solution of hydrogen bromide and the mix soobtained agitated for about 30 minutes at 0 C. To the mix is then addedan equal volume of water and the composite so obtained extracted withchloroform. The chloroform extract-s are combined, washed with water anddried over magnesium sulfate. Upon subjecting the dried chloroformsolution to vacuum distillation there is obtained 3.9 parts by weight ofa crystalline residue which upon tn'turating with diethyl ethercontaining a small amount of acetone yields dl- 3,11,20 triketo 16 bromol7 hydroxy 21 acetyloxy d -pregnene (M. P. 238240 C. withdecomposition).

Similarly the individual optically active isomers such as thenatural.modification of 3,11,20-triketo-16-halo-17e hydroxy-2l-acyloxy-l i-pregnene are obtained beginning due is then taken up with chloroform.The solution is with the appropriate individual optically active isomersof 3,11,20-t1iketo-16,l7 oxido-2l-acyloxy-h -pregnene.

In the next step of the process as afore schematically outlined thehalo-hydrin (Compound VII) is converted to the 21-acyl derivative of3,l1,20-triketo-17,2ldi hydroxy-N-pregnene (Compound VIII) byde-halogenating or reducing the former with a metallic reducing agentsuch as cobalt zinc, nickel, etc.

As illustrative of this step is the following:

Example V11 To a suitable reaction vessel containing 10 parts by weightof Raney nickel is added and intimately mixed 25 parts by Weight ofwater and 2 parts by Weight 'of dl-f' 3,11,20 triketo l6 bromo l7hydroxy 21 acetyle oxy-K -pregnene and the reaction mix so 'obtaincd'r'cfiuxed in an atmosphere of nitrogen for about 4 hours; The reaction mixso obtained is filtered and the residue washed with warm acetone. Thewashings and original filtrate are combined and subjected to vacuumdistilla: tion. The resultant residue is taken up with chloroform andthe solution so formed washed with water and dried. The dried solutionis then subjected to vacuum distillation whereupon there is recoveredapproximately 1.9 parts by Weight of a white crystalline residue whichupon triturating with diethyl ether-acetone mix yields 41;-3,11,2O-triketo-l7-hydroxy-2lacetyloxy-K pregnene (M;. P. 240-243 C.)which compound is identicalwith the acetate of 'racemic (dl) cortisone.'3 if'iiiil Similarly the individual optically active isomers such asacyl derivatives of the natural modification of 3,11,20-triketo-l7,21-dihydroxy Z -pregnene are obtained beginning with theappropriate optically active isomers of 3,11,20-triketo 16 bromo 17hydroxy-2l-acyloxy 'A' pregnene. The 21-acyl derivative of the naturalmodification of 3,11,20-triketo-17,2l-dihydroxy-K -pregnene according toinfrared spectrum, melting point and optical rotation is identical withthe corresponding acyl derivative of natural cortisone. Thusly it is tobe understood that the optically active isomers referred to herein asthe natural modification are those which through the course of reactionsas afore schematically outlined provide for the acyl derivatives ofnatural cortisone.

The 17-formyl-cyclopent-16-eno-10,13-dimethyl-K-dodecahydrophenanthren-IUl-diones (Compound I of the schematic diagram)are new compounds and as illustrative of their preparation butparticularly the natural modification of 3,1l-diketo-l7-formyl-2S-androstadiene is the following:

The process initially comprises (as described by W. S. Knowles, inUnited States application Ser. No. 345,699, filed March 30, 1953, now U.S. Patent No. 2,760,975) the preparation of the natural modification of3-keto- 16,17rdihydroxy 5 -D-homoandrostadiene by a process comprising(a) reacting the levo-rotat-ory form of anti trans 1,8a dimethyl,'A'-decahydrophenanthren-2-one, prepared by the hydrogenation of thelevorotatory form of anti-trans-1,8a-dimethyl,-decahydrophenanthren-Z-one in the presence of palladium, with ethylformate in the presence of sodium methylate to form the1,8a-dimethyl-3-[(hydroxy) methylene], 5 -decahydrophenanthren-Z-onederivative, (b) condensing 1,8a dimethyl 3 [(hydroxy) methylene], d-decahydrophenanthren-2-one derivative with N- methylaniline to form the1,8a-dimethyl-3-[(N-methyl anilino) methylene], K-decahydrophenanthren-Z- one derivative, (c) reacting the1,8a-dimethyl-3-[(methylanilino) methylene], K -decahydrophenanthren-Z-one derivative with acrylonitrile under alkaline conditions andconverting the product so obtained by vigorous alkaline hydrolysis tothecorresponding 1,8a-dimethyl-1-(flcarboxyethyl), '3-decahydrophenanthren-2- one 00m- 7 pound; (d) heating the1,8a-dimethyl-l-(fl-carboxyethyl), A -decahydrophenanthren-lone compoundwith acetic anhydride in the presence of sodium acetate to form the3-keto-K 4-oxa-D-homoandrostatriene derivative, (e) reacting the3-iteto-n -4-oxa-D-homoandrostatriene derivative with a methyl magnesiumhalide in the presence of ether, decomposing the addition product soobtained by acidification with mineral acid, (f) treating the ethersolubles of the acidified mix with an alkali metal hydroxide andrecovering therefrom the corresponding 3-keto-7a' -D-homoandrostatrienederivative, (g) oxidizing the 3-keto-h -Dmomoandrostatriene derivativeso formed with iodine in the presence of silver acetate, (11)hydrolyzing the product so obtained to. form the corresponding naturalmodification of 3-ket'o- 16,17 dihydroxy A4301) D homoandrostadiene. Theacetonide of the natural modification of S-keto-l 6,17- dihydroxy-ZS-D-homoandrostadiene is then prepared by reacting the glycol withacetone in the presence of anhydrous copper sulfate. The acetonide isthen converted to the natural modification of 3,1l-diketo-17- formyl-A-androstadiene by the process as described by W. S. Knowles in UnitedStates application Ser. No. 355,399, filed May 15, 1953, now U. S.Patent No. 2,736,732, which process comprises (a) reacting 3-keto-16,17-dihydroxy id -D-homoandrostadiene acetonide with hypomobromousacid, (b) oxidizing the 9-bromo- II-hydroxy addition product so obtainedin an anhydrous medium with a complex of chromium oxide and pyridine,(c) admixing the oxidized product so obtained with zinc and acetic acidto effect formation of 3,1 1-diketo-16,17-

3 dihydroxy K*-D-homoandrostene acetonid'e, (d) hydrolyzing theacetonide so obtained to form the free glycol with dilute mineral acid,(e) oxidizing the glycol so obtained with periodic acid, (f) heating theoxidized prodnot so obtained in the presence of piperidine acetate, (g)and recovering the natural modification of 3,1l-diketo- 17-formyl-A-androstadiene.

This application is a division of co-pending application Serial No.361,828, filed June 15, 1953, now U. S. Patent No. 2,759,928.

While this invention has been described with respect to certainembodiments it is not so limited and it is to be understood thatmodifications and variations obvious to those skilled in the art may bemade without departing from the spirit orscope of this invention.

What is claimed is:

A -(diazoacetyl) cy lopentano16,17-0xido-10A3diw medo -A dodecahydr phenn h n-it,1l dione of. the structural formula No references cited.

